SUMMARY The NIMH transgenic core facility has several major functions: 1) to produce transgenics for neuroscience research at NIH 2) develop new transgenic techniques and model systems 3) support research with associated techniques in genetic research in neuroscience and 4) engage in collaborative projects that promote genetic approaches to neuroscience research. 1) Production Meterics of production over the past year included: a) 23 transgenic mouse projects produced by oocyte injection, with multiple lines produced for each project. b) 14 transgenic rat projects produced by oocyte injection, with multiple lines produced for each project. c) 14 mouse projects have first altering the genes of ES cell and then using those to produce mice. 2) Development Over the last year projects to allow more productive methods have been developed. Two notable projects are a) in collaboration with NIDA the core has development of a panel of rats that produce recombinases or optogenetic probes under the control of transcriptional promoters that are specific for subpopulations of neurons. Fourteen of those lines have been produced, eight of which are being characterized by end users and will available for distribution. b) developing methods to produce transgenic marmosets. Over the past year rapid progress in developing techniques to produce transgenic marmosets have been made in the core facility. The methods to produce an excess of embryos, to optimize surgical procedures to harvest those embryos most efficiently, to culture those embryos, develop transgenic lentivirus, infect embryos, transfer those embryos into recipient females using ultrasound visualization and develop tissue culture methods for primary marmoset cells have been developed. This extensive effort has set the stage for several projects for NIH researchers to use these transgenic animals in basic research in the intramural program. 3) Technical Support a) 211 transgenic rodent lines have been archived by cryopreserving germ cells or embryos. b) 87 lines have been rederived, by transferring lines from pathogen bearing animals into those with defined health status. c) transgenic project design and assistance have continued to be significant to NIH neuroscience labs without experience in producing transgenic animals. 4) Collaborative projects: below is a list of projects that have been initiated in 2011, or have continued from last year. Stress and neurogenesis: Mice produced in the transgenic core were described in a paper that showed the necessity of neurogenesis for the normal response to stress. Since it has been shown that stress reduces neurogenesis this newer result indicates that a cycle of increasing stress. Learning and memory: The effect of specific and tightly controlled protein synthesis on learning and memory was studied. In addition, transgenic mouse models have been used to show the rrole of specific peptide-expressing cells to influence the link between fear and behavior and learning. Manipulating circuitry: Mice have been produced for two separate laboratories which have specific neurons that could be rendered transiently inactive by light activated ion channels. Those laboratories are investigating different neural circuits that are active in learning and addiction. Addictive and reward behavior: Lines of transgenic rats that express GFP in response to afferent input activation of the fos gene were generated in the core facility. These rats are being used by Bruce Hopes laboratory in NIDA to study patterns of neural activity in response to addictive drugs and most recently in the role of stress in reducing the re-establishment of rewarded behavior. . Mucolipidosis IV: The mouse model of this disease resulted from a long-standing collaboration with the Slaugenhaupt laboratory and has continued to yield results, including a description of the neuropathy that may be associated with this disease. The core facility continues to distribute these animals. More specific alterations of the Mcoln1 gene in transgenic animals are being planned. mRNA trafficking in neurons: An RNA stem loop structure is necessary for the translocation of message to specific cell compartments of the neuron. Mice that over express mRNA with this structure have been produced in an effort to disrupt this translocation machinery. By expressing this transgenic mRNA in different neuronal subtypes, the role for this mechanism for normal function is being studied. In addition this mechanism could be useful to target specific messages specifically to the synapse. Familial dysautonomia: Another collaboration with the Slaugenhaupt lab resulted in a model for this disease. Lines carrying either a human normal or disease gene are being created in the core. These lines are crossed into a null line to replace the endogenous IKBKAP gene with its human disease equivalent.